Oral ingestion is one of the primary routes used for drug administration. This route provides a convenient method of effectively achieving both local and systemic effects. The properties of Lanthanum make it a good candidate as a phosphate binder. It has a high affinity for binding phosphorous and in the form of its carbonate salt, has a low solubility that limits gastrointestinal absorption. In the presence of HCl acid in the stomach, a proportion of administered Lanthanum carbonate is converted to the more highly soluble chloride salt with the release of carbon dioxide.
The commercially available composition of Lanthanum is a chewable tablet and is marketed under the brand name of FOSRENOL® in strengths of 500 mg, 750 mg and 1000 mg strengths.
FOSRENOL® inhibits absorption of phosphate by forming highly insoluble Lanthanum phosphate complexes, consequently reducing both serum phosphate and calcium phosphate product. In vitro studies have shown that in the physiologically relevant pH range of 3 to 5 in gastric fluid, Lanthanum binds approximately 97% of the available phosphate when Lanthanum is present in a two-fold molar excess to phosphate.
A stable pharmaceutical composition does not exhibit substantial decomposition of the active pharmaceutical ingredient during the time between the manufacture of the composition and its use by a patient. Lanthanum carbonate and a number of other drugs suffer from instability problems because the active pharmaceutical ingredient rapidly degrades in the presence of water or moisture. Lanthanum carbonate compositions tend to degrade, with formation of lanthanum hydroxycarbonate.
Palatability and “mouth feel” are extremely important factors in formulating high dose insoluble drugs, especially, if the composition is intended to be a chewable formulation. Insoluble materials usually have both an unpleasant mouth feel and an unpalatable taste due to chalkiness, grittiness, & dryness properties of these materials.
It is known that tablet blends may be dry mixed, dry-granulated or wet-granulated before tableting. The choice of the processing procedure viz., (dry mixing, dry granulation, wet granulation) depends on the properties of the drug and the chosen excipients. Generally, a dry manufacturing process is thought to be preferable for moisture-sensitive drugs.
JP 62-145024 discloses Lanthanum carbonate. Example 11 therein discloses La2(CO3)3H2O, i.e. the monohydrate.
U.S. Pat. No. 5,968,976 discloses pharmaceutical compositions for the treatment of hyperphosphataemia comprising Lanthanum carbonate hydrate where Lanthanum has three to six molecules of water. This document states that certain forms of Lanthanum carbonate exhibit improved performance i.e. higher phosphate removal, specifically Lanthanum carbonates having 3 to 6 molecules of water per molecule of Lanthanum carbonate, over then available standard commercial Lanthanum carbonate, which the inventors believed was the octahydrate form, and over La2(CO3)3H2O i.e. monohydrate form or similar compounds.
U.S. Pat. No. 7,192,609 and US 2007/116782 disclose a method of preventing or treating urolithiasis i.e. kidney stones using nontoxic salts of rare earth metal ions e.g., Lanthanum salts, to bind dietary oxalate and preventing its absorption into the gastrointestinal tract. They also disclose that the hydration state of the Lanthanum salt is important; especially hydrates with waters of hydration of less than 7 moles water per mole of salt, and preferably the salts should contain 3 to 5 moles of water.
U.S. Pat. No. 7,381,428 discloses stabilized Lanthanum carbonate compositions, essentially prepared by dry mixing and compression of Lanthanum carbonate and stabilizers along with pharmaceutically acceptable additives, where monosaccharide or disaccharides are used as stabilizing agent to control/avoid the generation of hydroxycarbonate impurity in the composition.
U.S. application No: 2005/0079135 discloses chewable pharmaceutical compositions, containing Lanthanum carbonate having 3 to 8 molecules of water and the process of making pharmaceutical composition which involve dry mixing the ingredients and directly compressing the powder mixture or a slugging method or a roller compaction method.
These afore-mentioned prior art can be summarized as follows:                a) Lanthanum carbonate having a hydration between 3 to 6 water molecules is preferred;        b) Avoidance of water/wet granulation and a preference towards dry methods—compaction/direct compression is noticed;        c) Monosaccharide or disaccharide excipients are the preferred stabilizing agents to avoid/lower generation of hydroxycarbonate impurity.        
There is a need in the art to provide stable and cost effective oral pharmaceutical composition comprising Lanthanum carbonate, where the composition is prepared utilizing alternative techniques and still prevents degradation of Lanthanum carbonate as current regulatory requirements preclude detectable decarboxylation for administration to patients.
The present invention is based on the finding that a stable, effective solid oral dosage form of Lanthanum carbonate can be prepared even with wet granulation technique and a high hydration state Lanthanum carbonate drug. Lanthanum carbonate used in the instant invention is in high hydration state, but still the composition prepared according the invention has comparable or higher in-vitro phosphate binding, as that of FOSRENOL®. The composition prepared according to the invention has a high load of Lanthanum carbonate, approximately more than 60% by weight of the composition, preferably between 65% to about 80% by weight of the composition. Also, a finer sized lanthanum carbonate is practically preferred for use in the composition. Drug particles having d (0.9) not more than 110 microns are preferred.